NT-3 induces structural and functional modification of synapses through distinct

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J Cell Biol. 2006 Dec 18;175(6):1029-42.

Neurotrophin 3 induces structural and functional modification of

synapses through distinct molecular mechanisms.

Je HS, Yang F, Zhou J, Lu B.

Section on Neural Development and Plasticity, National Institute of

Child Health and Human Development, and 2Gene, Cognition and

Psychosis Program, National Institute of Mental Health, National

Institutes of Health, Bethesda, MD 20892.

The mechanisms by which neurotrophins elicit long-term structural

and functional changes of synapses are not known. We report the

mechanistic separation of functional and structural synaptic

regulation by neurotrophin 3 (NT-3), using the neuromuscular synapse

as a model. Inhibition of cAMP response element (CRE)-binding

protein (CREB)-mediated transcription blocks the enhancement of

transmitter release elicited by NT-3, without affecting the synaptic

varicosity of the presynaptic terminals. Further analysis indicates

that CREB is activated through Ca(2+)/calmodulin-dependent kinase IV

(CaMKIV) pathway, rather than the mitogen-activated protein kinase

(MAPK) or cAMP pathway. In contrast, inhibition of MAPK prevents the

NT-3-induced structural, but not functional, changes. Genetic and

imaging experiments indicate that the small GTPase Rap1, but not

Ras, acts upstream of MAPK activation by NT-3. Thus, NT-3 initiates

parallel structural and functional modifications of synapses through

the Rap1-MAPK and CaMKIV-CREB pathways, respectively. These findings

may have implications in the general mechanisms of long-term

synaptic modulation by neurotrophins.